Cu(OTf)2-Catalyzed Intramolecular Radical Cascade Reactions for the Diversity-Oriented Synthesis of Quinoline-Annulated Polyheterocyclic Frameworks

Article abstract of DOI:10.1021/acs.orglett.1c00129

Compound libraries with high levels of structural diversity and novelty could cover underexploited chemical space and thus have been highly pursued in drug discovery. Herein, we report the first Cu(OTf)2-catalyzed intramolecular radical cascade reactions

Full text of DOI:10.1021/acs.orglett.1c00129

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Letter
Cu(OTf)2‑Catalyzed Intramolecular Radical Cascade Reactions for the
Diversity-Oriented Synthesis of Quinoline-Annulated
Polyheterocyclic Frameworks
Shuo Yuan, Jingya Zhang, Danqing Zhang, Donghui Wei, Jiahui Zuo, Jian Song, Bin Yu,*
and Hong-Min Liu*
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ABSTRACT: Compound libraries with high levels of structural diversity and novelty could cover underexploited chemical space
and thus have been highly pursued in drug discovery. Herein, we report the first Cu(OTf)2-catalyzed intramolecular radical cascade
reactions that enable the diversity-oriented synthesis of quinoline-annulated polyheterocyclic compounds (7 unique scaffolds, 66
examples) in an efficient manner. This work demonstrates an alternative route to access the natural product- and druglike compound
collection with high levels of structural diversity and novelty.
he privileged polyheterocyclic compounds containing a
quinoline fragment are widely present in numerous
distomadine A (a tetracyclic alkaloid isolated from Pseudodis-
toma aureum with antifungal activity)7 (Figure 1A). In
addition, quinoline-containing polyheterocyclic fragments are
also prevalent in bioactive molecules, such as torin 1 (a potent
and selective mTOR inhibitor),8 topovale (a Top1 targeting
antitumor drug),9 KuFal194 (a highly potent and selective
DYRK1A inhibitor),10 and QL47 (a potent, selective and
irreversible BTK inhibitor)11 (Figure 1B). Because of the
unique structural features and interesting biological profiles of
quinoline-containing polyheterocyclic scaffolds, several syn-
thetic strategies have been developed for the construction of
these structurally complex and biologically important scaffolds
in recent decades; two main strategies include (a) transition-
metal-catalyzed cyclization reactions of quinoline bearing
substrates12−14 and (b) transition-metal-catalyzed domino
cascade reactions forming the quinoline ring system.15−17
Alkynes have been extensively used in organic synthesis,
particularly for cyclization reactions.18−21 In 2012, Zhu and co-
workers successfully obtained indolo[3,2-c]isoquinolinones
through Pd-catalyzed intramolecular cascade reactions of
alkynes, in which amination, N-demethylation, and amidation
T
natural products and bioactive molecules, and such com-
pounds have proven to possess a wide variety of pharmaco-
logical properties, such as anticancer, antiviral, and antiangio-
genic activity (Figure 1).1−3 Representative quinoline-contain-
ing natural products are trisphaeridine (an alkaloid isolated
from amaryllidaceae species with potential antitumor activity),4
camptothecin (a topoisomerase inhibitor isolated from
camptotheca acuminate with remarkable anticancer activity),5
fagaronine (a benzophenanthridine alkaloid found in zanthox-
ylum zanthoxyloides with potential antimalarial activity),6 and
Received: January 13, 2021
Published: February 9, 2021
Figure 1. Selected quinoline-fused polyheterocyclic natural products
and bioactive molecules.
https://dx.doi.org/10.1021/acs.orglett.1c00129
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1445−1450
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were involved (Scheme 1A).22 In 2016, Du et al. successfully
achieved stepwise synthesis of indolo[3,2-c]isocoumarins
diarylacetylenes and aromatic aldehydes using I2 as an oxidant
(Scheme 1D). Of note, the structural diversity depends on the
neighboring functional groups and thus is controllable. This
feature could be used to generate diverse compound collection,
which may have potential applications in drug discovery.
Initially, methyl 2-((2-aminophenyl)ethynyl)benzoate 1a
and 4-chlorobenzaldehyde 2a were chosen as model substrates
to optimize the reaction conditions (Table 1). Upon treatment
Scheme 1. Intramolecular Cascade Reactions of Alkynes
Enabling the Construction of Diverse Polyheterocyclic
Scaffolds
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
solvent
additive
oxidant
3a (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
CF3COOAg
Cu(OTf)2
CuI
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
DMF
MeCN
THF
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TsOH
TsOH
TsOH
TsOH
TsOH
AcOH
TfOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
16
12
37
4
Ni2SO4
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
18
25
20
5
6
ND
9
10
11
12
13
14
15
16
17
18
19
20
21
c
5
d
I2
85 (79)
PhIO
PIDA
PIFA
I2
I2
I2
6
4
9
32
40
58
Cu(OAc)2
Cu(acac)2
Cu(OTf)2
Cu(OTf)2
e
I2
I2
75
f
55
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst (20 mol
%), solvent (2 mL), additive (0.25 mmol), oxidant (0.5 mmol), 90
through intramolecular trans-aminocarboxylation of alkynes
(Scheme 1B).23 In 2018, Xu et al. reported a gold-catalyzed
bicyclization of diarylacetylenes for the synthesis of indole
annulated tetracyclic compounds (Scheme 1C).24 These
examples have demonstrated that trapping alkynes by
neighboring nucleophilic groups is a viable strategy that
enables rapid access to pharmacologically relevant polyheter-
ocyclic scaffolds through cascade reactions.25,26 To date,
although several protocols about the efficient synthesis of
polyheterocyclic scaffolds through alkyne-based cascade
reactions have been disclosed, the versatile one-pot synthetic
strategy for the construction of diverse quinoline-containing
polyheterocyclic scaffolds is still rare. Moreover, achieving high
levels of structural novelty and diversity in an efficient manner
is challenging and highly desirable, such compound library
covers underexplored chemical space and thus is a key to
success in new drug discovery campaign. In continuation with
our previous work on the synthesis of biologically important
heterocycles,27−33 we herein report the Cu(OTf)2-catalyzed
domino 6-endo-dig cyclization/C−C coupling reaction se-
quence that enables the efficient synthesis of architecturally
diverse and novel quinoline-annulated polyheterocyclic scaf-
folds (7 unique scaffolds, 66 examples, up to 86% yield) from
b
°C, 3 h. NMR yields determined by 1H NMR using triphenyl-
c
d
methane as an internal standard. ND = not detected. Isolated yield.
e
f
10 mol % of catalyst was used. 5 mol % of catalyst was used.
with 20 mol % Pd(OAc)2 and 0.5 equiv of TsOH in DCE (2
mL) at 90 °C for 3 h, the desired quinoline-annulated
tetracyclic compound 3a was obtained in 16% yield (Table 1,
entry 1). We next screened other metal catalysts (Table 1,
entries 2−5), showing that Cu(OTf)2 was the optimal catalyst,
giving 3a in 37% yield (Table 1, entry 3). When AcOH and
TfOH were used as acidic additives, compound 3a was
obtained in 18% and 25% yield, respectively (Table 1, entries 6
and 7). We also found that the solvent effect was remarkable:
replacing DCE with toluene, DMF, MeCN, THF, and MeOH
led to significantly diminished yields (Table 1, entries 8−12).
To our satisfaction, addition of I2 significantly improved the
reactivity, giving 3a in 85% yield (Table 1, entry 13), while
other hypervalent iodine reagents such as iodosobenzene
(PhIO), (diacetoxyiodo)benzene (PIDA), and phenyliodine
bis(trifluoroacetate) (PIFA) were found to be less efficient,
giving 3a in <10% yields (Table 1, entries 13−16). It should be
noted that in the absence of Cu(OTf)2, compound 3a was
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obtained in 32% yield (Table 1, entry 17). Replacement of
Cu(OTf)2 with Cu(OAc)2 or Cu(acac)2 caused significantly
decreased yields, compound 3a was generated in 40% and 58%
yields, respectively (Table 1, entries 18 and 19). A lower
catalyst loading of 10 and 5 mol % furnished 3a in 75% and
55% yield, respectively (Table 1, entries 20 and 21). According
to the above optimizations, the optimal reaction conditions
were methyl 2-((2-aminophenyl)ethynyl)benzoate 1a (0.5
mmol), 4-chlorobenzaldehyde 2a (1.0 mmol), Cu(OTf)2 (20
mol %), TsOH (0.25 mmol), I2 (0.5 mmol), DCE (2 mL), 90
°C, 3 h (Table 1, entry 13).
Scheme 2. Substrate Scope of Aldehydes and
Diarylacetylenes for the Synthesis of Quinoline-Annulated
Tetracyclic Scaffolds
a b
,
With the optimal reaction conditions in hand, we next
examined the scope of 2-((2-aminophenyl)ethynyl)benzoates
and aromatic aldehydes. As shown in Scheme 2A, the
quinoline-annulated polyheterocyclic compounds were ob-
tained in moderate to good yields (40−86%). For halogen-
substituted aromatic aldehydes, the corresponding products
3a−3m were provided in good yields (56−80%). The halogen
atoms were well tolerated and could be used for further
functionalization. Mostly due to the steric hindrance, the
compounds (e.g., 3b, 3e, 3g, 3j) bearing an ortho substituent
were obtained in relatively lower yields. In general, both
electron-deficient (−CF3, −CN, −CHO) and electron-rich
(−Me, −Et, −iPr, −tBu, −OMe, −OH) aromatic aldehydes
proceeded smoothly under the optimized reaction conditions
and furnished the desired compounds 3o−3ac in moderate to
good yield (40−84%). Compounds 3s and 3aa bearing the
oxidizable formaldehyde and phenolic OH groups were
generated in relatively lower yields. In addition, the naphthyl
aldehydes, 4-phenylbenzaldehyde, and heteroaromatic alde-
hydes were also compatible with our protocol and delivered
the corresponding polyheterocyclic compounds 3ad−3ah in
good yield (77−86%). To showcase the synthetic practicality,
the reactions for the synthesis of compounds 3b and 3r were
performed on a 1.0 mmol scale, providing the desired products
in 60% and 66% yields, respectively. The crystal structure of 3a
was also determined by the X-ray crystallographic analysis
(CCDC: 1921863). We here demonstrate that diverse
functional groups such as amine, ester, and aldehyde in
substrates are well tolerated under the optimized reaction
conditions and could be integrated in an efficient manner to
form quinoline-annulated tetracyclic scaffolds. Besides, the
scope of diarylacetylenes was also explored to showcase the
generality of our protocol. As shown in Scheme 2B, various
substituents on both phenyl rings of diarylacetylenes were well
tolerated, giving the desired products 4a−4v in moderate to
good yields (45−83%) under the optimal reaction conditions.
As shown in Scheme 2, the core scaffold depends on the
functional ester group. Encouraged by the preceding results, it
can be speculated that replacement of ester with other
nucleophilic functional groups may afford novel polyheter-
ocyclic scaffolds. As shown in Scheme 3A, diarylacetylenes
bearing different functional groups (e.g., −CONHPh,
−CH2OH, phenolic OH, and amine) gave the corresponding
products with high levels of structural diversity and novelty
under the optimal conditions. Specifically, the quinoline-fused
isoquinolinone scaffolds (5a,b) synthesized from 2-((2-
aminophenyl)ethynyl)-N-phenylbenzamide widely exist in
topoisomerase inhibitors and other bioactive molecules
(Figure 1).34−36 For diarylacetylenes with the hydroxyl methyl
and phenolic OH groups, the quinoline-fused isochrones 5c,d
and quinoline-fused benzofurans 5e,f were obtained in
moderate to good yields through an intramolecular O-attack
a
Conditions: 1a (0.5 mmol), 2 (1.0 mmol), Cu(OTf)2 (20 mol %),
b
TsOH (0.25 mol), I2 (0.5 mmol), DCE (2 mL), 90 °C, 3 h. Isolated
yields. Conditions: 1a (1 mmol), 2 (2.0 mmol), Cu(OTf)2 (20 mol
%), TsOH (0.5 mol), I2 (1 mmol), DCE (5 mL), 90 °C, 3 h. 0.5
mmol of 2 was used.
c
d
pathway. Besides, we also found that N,N-dimethylamine could
be employed as a nucleophile to produce the quinoline-
annulated indoles 5g,h through the N-attack pathway. The
pyridine-fused indole scaffold, also known as γ-carboline, is an
interesting structural motif existed in natural products and
bioactive molecules with diverse pharmacological activ-
ities.37−39 To further increase the scaffold diversity, the
diarylacetylene 1b bearing a terminal alcohol group was
used, giving the desired tetrahydropyran-fused quinoline 6a in
80% yield under the optimal conditions (Scheme 3B). The
tricyclic heterofused quinoline 6a is a key intermediate for the
synthesis of druglike compound A with multitrypanosomatid
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Scheme 3. Diversity-Oriented Synthesis of New Quinoline-
Annulated Polyheterocyclic Scaffolds
Scheme 4. Control Experiments
a b
,
Based on our observations and previous reports,41−44 the
proposed mechanism for the synthesis of quinoline-annulated
polyheterocyclic scaffolds is shown in Scheme 5. Initially, the
Scheme 5. Plausible Reaction Mechanism
a
Conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OTf)2 (20 mol %),
b
TsOH (0.25 mol), I2 (0.5 mmol), DCE (2 mL), 90 °C, 3 h. Isolated
yields. Conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OTf)2 (20 mol
c
%), TsOH (0.5 mol), I2 (0.05 mmol), DCE (2 mL), 90 °C, 6 h.
activity.40 This protocol provides an alternative method to
synthesize compound A and analogues for biological testing.
Similarly, compound 1c reacted with 4-hydroxylbenzaldehyde
2d smoothly, affording 7a in 77% yield (Scheme 3C). Of note,
the electron-rich phenyl ring served as an intramolecular
nucleophile for the cascade reactions, and only 10 mol % of I2
was used. Further investigation on using electron-rich arenes as
nucleophiles for intramolecular cascade reactions is undergoing
in our lab and will be reported in due course. The crystal
structures of 5h and 7a were further confirmed by the X-ray
analysis (5h, CCDC: 1964272; 7a, CCDC: 1964273).
Collectively, we envisioned that the copper catalysis developed
herein achieved the diversity-oriented synthesis of new
quinoline-fused polyheterocyclic frameworks present in natural
products and bioactive molecules, and the structural diversity
and novelty depended on the types of functional groups. It is
anticipated that more novel scaffolds could be generated by
installing other nucleophilic groups on the phenyl rings.
The control experiments were conducted to gain mecha-
nistic insight into this cascade reaction. As shown in Scheme 4,
the radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) completely suppressed the reaction, while butylhy-
droxytoluene (BHT) also inhibited the reaction, giving the
intermediate M0 is generated in situ from methyl 2-((2-
aminophenyl)ethynyl)benzoate (1a) and benzaldehyde (2n)
through TsOH-promoted condensation. Then the intermedi-
ate M0 undergoes a cooper salt promoted one-electron
oxidation to form a radical cation M1. Subsequent intra-
molecular radical addition into the CC bond of M1 affords a
radical M2, which then adds onto intramolecular imine
through nucleophilic insertion to give a cyclized radical M3.
The nitrogen radical would be trapped by iodine radical
generated from the oxidation of iodide, generating the complex
M4. Finally, a hydrogen iodide elimination step furnishes the
alkenylation product 3n. Through the Cu-catalyzed cascade
reactions, the diverse quinoline-annulated polyheterocyclic
frameworks are efficiently constructed, in which one C−X (X
= C, N, or O) bond, one CN bond, one C−C bond, and two
new ring systems are formed simultaneously.
1
desired product 3a in only 22% yield (detected by H NMR
using triphenylmethane as an internal standard), significantly
lower than that under the optimal conditions. The data suggest
that the Cu-catalyzed intramolecular cascade reactions involve
a radical process.
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In conclusion, we have developed the first Cu(OTf)2-
catalyzed intramolecular radical domino reactions that enable
the efficient construction of structurally novel and diverse
quinoline-annulated polyheterocyclic scaffolds from readily
available diarylacetylenes and aromatic aldehydes. These
polyheterocyclic scaffolds show high levels of structural
diversity and novelty and have been found in numerous highly
valuable natural products and bioactive molecules. Of note, the
scaffold diversity, a central element in diversity-oriented
synthesis, solely depends on the neighboring functional groups
and thus is controllable. The compound library may have
potential applications in new drug discovery.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (Nos. 81773562 and 81973177),
the Program for Science & Technology Innovation Talents in
Universities of Henan Province (No. 21HASTIT045), and the
China Postdoctoral Science Foundation (Nos. 2018M630840,
and 2019T120641).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00129.
1
Experimental procedures, characterization data, and H
NMR, 13C NMR spectra for new compounds (PDF)
́
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obtained free of charge via www.ccdc.cam.ac.uk/data_request/
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AUTHOR INFORMATION
■
Corresponding Authors
Bin Yu − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China; orcid.org/0000-
0002-7207-643X; Email: yubin@zzu.edu.cn
Hong-Min Liu − School of Pharmaceutical Sciences,
Zhengzhou University, Zhengzhou 450001, China;
orcid.org/0000-0001-6771-9421; Email: liuhm@
zzu.edu.cn
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Authors
Shuo Yuan − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China; orcid.org/0000-
0002-4273-5625
Jingya Zhang − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China
Danqing Zhang − School of Pharmaceutical Sciences,
Zhengzhou University, Zhengzhou 450001, China
Donghui Wei − College of Chemistry, and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001,
China; orcid.org/0000-0003-2820-282X
Jiahui Zuo − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China
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Jian Song − School of Pharmaceutical Sciences, Zhengzhou
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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